Mathematical characterization of population dynamics in breast cancer cells treated with doxorubicin

Abstract

The development of chemoresistance remains a significant cause of treatment failure in breast cancer. We posit that a mathematical understanding of chemoresistance could assist in developing successful treatment strategies. Towards that end, we have developed a model that describes the cytotoxic effects of the standard chemotherapeutic drug doxorubicin on the MCF-7 breast cancer cell line. We assume that treatment with doxorubicin induces a compartmentalization of the breast cancer cell population into surviving cells, which continue proliferating after treatment, and irreversibly damaged cells, which gradually transition from proliferating to treatment-induced death. The model is fit to experimental data including variations in drug concentration, inter-treatment interval, and number of doses. Our model recapitulates tumor cell dynamics in all these scenarios (as quantified by the concordance correlation coefficient, CCC > 0.95). In particular, superior tumor control is observed with higher doxorubicin concentrations, shorter inter-treatment intervals, and a higher number of doses (p < 0.05). Longer inter-treatment intervals require adapting the model parameterization after each doxorubicin dose, suggesting the promotion of chemoresistance. Additionally, we propose promising empirical formulas to describe the variation of model parameters as functions of doxorubicin concentration (CCC > 0.78). Thus, we conclude that our mathematical model could deepen our understanding of the cytotoxic effects of doxorubicin and could be used to explore practical drug regimens achieving optimal tumor control.

Computational identification of surface markers for isolating distinct subpopulations from heterogeneous cancer cell populations

“…The copyright holder for this preprint (which this version posted June 2, 2024. ; https://doi.org/10.1101/2024.05.28.596337 doi: bioRxiv preprint perturbations skewing interpretation of bulk results. Subpopulations have been characterized in cell lines through different modalities [27][28][29][30]35,45,46 , but these studies may have isolated rare subsets of cells. In contrast, clusterCleaver delivers a workflow for discovering and isolating subpopulations starting from full knowledge of the transcriptomic diversity within cell lines by starting at scRNA-seq.…”

“…Numerous studies have been performed on cell lines without knowledge of their underlying population structure, yet subpopulations of cells may behave disparately under different culture conditions and perturbations skewing interpretation of bulk results. Subpopulations have been characterized in cell lines through different modalities 27–30,35,45,46 , but these studies may have isolated rare subsets of cells. In contrast, clusterCleaver delivers a workflow for discovering and isolating subpopulations starting from full knowledge of the transcriptomic diversity within cell lines by starting at scRNA-seq.…”

Games and the Treatment Convexity of Cancer

“…Another predator-prey mathematical model showed evidence of reciprocal antagonism at play within competition dynamics of parental and radiation-resistant cell lines [24]. These models have also been applied to endocrine therapy [25] and doxorubicin therapy [26,27] in breast cancer cell lines. There is also evidence of the existence of positive or cooperative ecological interactions in cancer: one recent study indicated paracrine signaling as a mechanism for which the dominant cell line's growth is enhanced by the presence of a co-cultured second cell line [28].…”

Hypophyllanthin and Phyllanthin from Phyllanthus niruri Synergize Doxorubicin Anticancer Properties against Resistant Breast Cancer Cells

“…Therefore, targeting drug resistance in breast cancer is crucial. 4 Mechanisms of DOX resistance are multifaceted and include upregulation of drug-resistant proteins, changes in membrane permeability of cancer cells, impairment of DNA damage repair mechanisms, and autophagy-arbitrated drug resistance. 5 Among these mechanisms, autophagy-mediated chemotherapy resistance has gained increasing attention.…”

“…Moreover, about 30–50% of metastatic breast cancer patients are irresponsive to the DOX treatment. Therefore, targeting drug resistance in breast cancer is crucial …”